This blog is devoted to the discussion of all aspects of synthetic organic chemistry and related sciences. Curly Arrow is run by a synthetic organic chemist based in Copenhagen, Denmark. Contributions from readers are always welcome and should be emailed to curlyarrow@gmail.com

Friday, December 15, 2006

How to make drugs

A couple of months ago I noticed this perspective in OBC (Org. Biomol. Chem., 2006, 4, 2337-234 7, DOI: 10.1039/b602413k). It provides a summery of the reactions used for the preparation of all drug candidates at AstraZeneca, GlaxoSmithKline and Pfizer in the UK.A nice read to for anyone who wants to know what is actually done on large scale or preparing for a process chemistry interview. A word of warning though, anyone who has spent a significant part of their life developing asymmetric methodology may be somewhat disheartened. It seems buying and resolving are still order of the day.S.

5 comments:

Some asymmetric methods are too tricky to be done in process or require lots of optimisation. But I think bigger problem is that there is not enough process chemists familiar/comfortable with these methods. When method is good and robust it will be implemented eventualy - asymmetric phosphine-Rh and Noyori Ru-asym transfer hydrogenation is being used on increasingly bigger scale. Process patents is part of the problem - Jacobsen for example licenced out his methods to Rhodia and now verybody has pay them royalties when using their methods commercialy. The same with Noyori.

I finally managed to read the paper Steve. Very interesting and surprising stuff. I was expecting to at least see some Sharpless asymmetric epoxidations or dihydroxylations happening but it seems they just go shopping for their chirality. Also I was surprised to see that C-C bond forming reactions account for a staggering 11% of the transformations. I was expecting a much lower number. Most of these are Pd-couplings (Suzuki in particular) but unbelievably there's Grignard reactions and directed lithiations going on. The reason for my surprise is that during the two years I worked in industry we managed to do one C-C bond in total between 5 synthetic organic chemists. We basically wanted to avoid C-C bond forming reactions at all cost because the easy ones involve metal catalysts and the hard ones are...well hard! During my two years in the company I only managed to make C-O, C-N, C-S, P-O and P-S bonds. I quite like the fact that they suggest methodologies that they would like to see developed in the future. I guess we'll all be working on catalytic, low waste acylations for the next couple of years! D!

It should be borne in mind that Process Chemists work under intense pressure, particularly on early phase projects, where time to kilos of target compound is the overriding concern. There is rarely time to develop complex catalytic asymmetric processes (which require catalyst/substrate opimisation)Often the ligands are not available in the required quantities or require more steps to prepare than the target itself. If a compound "makes it" to late phase then all avenues will be explored and the most cost-efficient method chosen for production.

Agree with Milkshake "Process patents is part of the problem ... [e]verybody has [to] pay them royalties when using their methods commercialy."

Daniel: "I was expecting to at least see some Sharpless asymmetric epoxidations or dihydroxylations happening but it seems they just go shopping for their chirality." see above.

Sort of agree with philoctates, "There is rarely time to develop complex catalytic asymmetric processes" ... In the early stages there is no point in developing a complex catalytic asymmetric process. Classical resolution esp if you are familiar with Shroder van Laar and if necessary Prigogine-Defay for a final polish is usually all that is necessary. Further a reasonable process can be developed reasonably quickly from an initial salt screen and DSC analysis.